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Abstract Background Previous studies have reported large socioeconomic inequalities in mortality from conditions amenable to medical intervention, but it is unclear whether these can be attributed to inequalities in access or quality of health care, or to confounding influences such as inequalities in background risk of diseases. We therefore studied whether inequalities in mortality from conditions amenable to medical intervention vary between countries in patterns which differ from those observed for other (non-amenable) causes of death. More specifically, we hypothesized that, as compared to non-amenable causes, inequalities in mortality from amenable causes are more strongly associated with inequalities in health care use and less strongly with inequalities in common risk factors for disease such as smoking. Methods Cause-specific mortality data for people aged 30–74 years were obtained for 14 countries, and were analysed by calculating age-standardized mortality rates and relative risks comparing a lower with a higher educational group. Survey data on health care use and behavioural risk factors for people aged 30–74 years were obtained for 12 countries, and were analysed by calculating age-and sex-adjusted odds ratios comparing a low with a higher educational group. Patterns of association were explored by calculating correlation coefficients. Results In most countries and for most amenable causes of death substantial inequalities in mortality were observed, but inequalities in mortality from amenable causes did not vary between countries in patterns that are different from those seen for inequalities in non-amenable mortality. As compared to non-amenable causes, inequalities in mortality from amenable causes are not more strongly associated with inequalities in health care use. Inequalities in mortality from amenable causes are also not less strongly associated with common risk factors such as smoking. Conclusions We did not find evidence that inequalities in mortality from amenable conditions are related to inequalities in access or quality of health care. Further research is needed to find the causes of socio-economic inequalities in mortality from amenable conditions, and caution should be exercised in interpreting these inequalities as indicating health care deficiencies.

Abstract Background Monitoring the time course of mortality by cause is a key public health issue. However, several mortality data production changes may affect cause-specific time trends, thus altering the interpretation. This paper proposes a statistical method that detects abrupt changes ("jumps") and estimates correction factors that may be used for further analysis. Methods The method was applied to a subset of the AMIEHS (Avoidable Mortality in the European Union, toward better Indicators for the Effectiveness of Health Systems) project mortality database and considered for six European countries and 13 selected causes of deaths. For each country and cause of death, an automated jump detection method called Polydect was applied to the log mortality rate time series. The plausibility of a data production change associated with each detected jump was evaluated through literature search or feedback obtained from the national data producers. For each plausible jump position, the statistical significance of the between-age and between-gender jump amplitude heterogeneity was evaluated by means of a generalized additive regression model, and correction factors were deduced from the results. Results Forty-nine jumps were detected by the Polydect method from 1970 to 2005. Most of the detected jumps were found to be plausible. The age- and gender-specific amplitudes of the jumps were estimated when they were statistically heterogeneous, and they showed greater by-age heterogeneity than by-gender heterogeneity. Conclusion The method presented in this paper was successfully applied to a large set of causes of death and countries. The method appears to be an alternative to bridge coding methods when the latter are not systematically implemented because they are time- and resource-consuming.

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Background: Enzyme-replacement therapy (ERT) in Pompe disease-an inherited metabolic disorder caused by acid α-glucosidase deficiency and characterized in infants by generalized muscle weakness and cardiomyopathy-can be complicated by immune responses. Infants that do not produce any endogenous acid α-glucosidase, so-called CRIM-negative patients, reportedly develop a strong response. We report the clinical outcome of our Dutch infants in relation to their CRIM status and immune response. Methods: Eleven patients were genotyped and their CRIM status was determined. Antibody formation and clinical outcome were assessed for a minimum of 4 years. Results: ERT was commenced between 0.1 and 8.3 months of age, and patients were treated from 0.3 to 13.7 years. All patients developed antibodies. Those with a high antibody titer (above 1:31,250) had a poor response. The antibody titers varied substantially between patients and did not strictly correlate with the patients' CRIM status. Patients who started ERT beyond 2 months of age tended to develop higher titers than those who started earlier. All three CRIM-negative patients in our study succumbed by the age of 4 years seemingly unrelated to the height of their antibody titer. Conclusion: Antibody formation is a common response to ERT in classic infantile Pompe disease and counteracts the effect of treatment. The counteracting effect seems determined by the antibody:enzyme molecular stoichiometry. The immune response may be minimized by early start of ERT and by immune modulation, as proposed by colleagues. The CRIM-negative status itself seems associated with poor outcome. [ABSTRACT FROM AUTHOR]

Background Infantile Pompe disease is a rare metabolic disease. Patients generally do not survive the first year of life. Enzyme replacement therapy (ERT) has proven to have substantial effects on survival in infantile Pompe disease. However, the costs of therapy are very high. In this paper, we assess the cost-effectiveness of enzyme replacement therapy in infantile Pompe disease. Methods A patient simulation model was used to compare costs and effects of ERT with costs of effects of supportive therapy (ST). The model was filled with data on survival, quality of life and costs. For both arms of the model, data on survival were obtained from international literature. In addition, survival as observed among 20 classic-infantile Dutch patients, who all received ERT, was used. Quality of life was measured using the EQ-5D and assumed to be the same in both treatment groups. Costs included the costs of ERT (which depend on a child's weight), infusions, costs of other health care utilization, and informal care. A lifetime time horizon was used, with 6-month time cycles. Results Life expectancy was significantly longer in the ERT group than in the ST group. On average, ST receiving patients were modelled not to survive the first half year of life; whereas the life expectancy in the ERT patients was modelled to be almost 14 years. Lifetime incremental QALYs were 6.8. Incremental costs were estimated to be € 7.0 million, which primarily consisted of treatment costs (95%). The incremental costs per QALY were estimated to be € 1.0 million (range sensitivity analyses: € 0.3 million - € 1.3 million). The incremental cost per life year gained was estimated to be € 0.5 million. Conclusions The incremental costs per QALY ratio is far above the conventional threshold values. Results from univariate and probabilistic sensitivity analyses showed the robustness of the results. [ABSTRACT FROM AUTHOR]

Background: Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome; MPS VI) is an autosomal recessive lysosomal storage disorder in which deficiency of N-acetylgalactosamine 4-sulfatase (arylsulfatase B; ARSB) leads to the storage of glycosaminoglycans (GAGs) in connective tissue. The genotype-phenotype correlation has been addressed in several publications but the picture is not complete. Since 2007, enzyme-replacement therapy (ERT) has been available for patients with MPS VI in the Netherlands. The purpose of our study was to learn more about the genotype-phenotype correlations in MPS VI and the antibody response to ERT with galsulfase (recombinant human arylsulfatase B). Methods: We identified ARSB mutations in 12 patients and used site-directed mutagenesis to study their effect. Antibody levels to galsulfase were measured using ELISA and a semi-quantitative immunoprecipitation method. We assessed the inhibitory effect of antibodies on galsulfase uptake and their effect on clinical outcome. in vitro Results: Five patients had a rapidly progressive phenotype and seven a slowly progressive phenotype. In total 9 pathogenic mutations were identified including 4 novel mutations (N301K, V332G, A237D, and c.1142 + 2 T > C) together composing 8 pathogenic genotypes. Most mutations appeared not to affect the synthesis of ARSB (66 kD precursor), but to hamper its maturation (43 kD ARSB). Disease severity was correlated with urinary GAG excretion. All patients developed antibodies to galsulfase within 26 weeks of treatment. It was demonstrated that these antibodies can inhibit the uptake of galsulfase . in vitro Conclusions: The clinical phenotypes and the observed defects in the biosynthesis of ARSB show that some of the mutations that we identified are clearly more severe than others. Patients receiving galsulfase as enzyme-replacement therapy can develop antibodies towards the therapeutic protein. Though most titers are modest, they can exceed a level at which they potentially affect the clinical outcome of enzyme-replacement therapy. [ABSTRACT FROM AUTHOR]

Background: Pompe disease is a rare metabolic myopathy for which disease-specific enzyme replacement therapy (ERT) has been available since 2006. ERT has shown efficacy concerning muscle strength and pulmonary function in adult patients. However, no data on the effect of ERT on the survival of adult patients are currently available. The aim of this study was to assess the effect of ERT on survival in adult patients with Pompe disease. Methods: Data were collected as part of an international observational study conducted between 2002 and 2011, in which patients were followed on an annual basis. Time-dependent Cox's proportional hazards models were used for univariable and multivariable analyses. Results: Overall, 283 adult patients with a median age of 48 years (range, 19 to 81 years) were included in the study. Seventy-two percent of patients started ERT at some time during follow-up, and 28% never received ERT. During follow-up (median, 6 years; range, 0.04 to 9 years), 46 patients died, 28 (61%) of whom had never received ERT. After adjustment for age, sex, country of residence, and disease severity (based on wheelchair and ventilator use), ERT was positively associated with survival (hazard ratio, 0.41; 95% CI, 0.19 to 0.87). Conclusion: This prospective study was the first to demonstrate the positive effect of ERT on survival in adults with Pompe disease. Given the relatively recent registration of ERT for Pompe disease, these findings further support its beneficial impact in adult patients. [ABSTRACT FROM AUTHOR]

An abstract of the article "Enzyme replacement therapy and fatigue in adults with Pompe disease" by Deniz Güngö, Juna de Vries, Esther Brusse, Michelle Kruijshaar, Linda van den Berg, Wim Hop, Arnold Reuser, Pieter van Doorn, Marloes Hagemans and Iris Plug is presented.

An abstract of the article "Impact of enzyme replacement therapy on survival in adults with Pompe disease" by Michelle Kruijshaar, Iris Plug, Ralph D'Agostino Sr., Marloes Hagemans, Arnold Reuser, Ans van der Ploeg and Deniz Güngör is presented.

Hip problems in Mucopolysaccharidosis type VI (MPS VI) lead to severe disability. Lack of data on the course of hip disease in MPS VI make decisions regarding necessity, timing and type of surgical intervention difficult. We therefore studied the development of hip pathology in MPS VI patients over time. Data were collected as part of a prospective follow-up study. Standardized supine AP pelvis and frog leg lateral radiographs of both hips were performed yearly or every 2 years. Image assessment was performed quantitatively (angle measurements) and qualitatively (hip morphology). Clinical burden of hip disease was evaluated by physical examination, six minute walking test (6MWT) and a questionnaire assessing pain, wheelchair-dependency and walking distance. A total of 157 pelvic radiographs of 14 ERT treated MPS VI patients were evaluated. Age at first image ranged from 2.0 to 21.1 years. Median follow up duration was 6.8 years. In all patients, even in the youngest, the acetabulum and os ilium were dysplastic. Coverage of the femoral head by the acetabulum improved over time, but remained insufficient. While the femoral head appeared normal in the radiographs at young age, the ossification pattern became abnormal in all patients over time. In all patients the distance covered in the 6MWT was reduced (median Z scores − 3.3). Twelve patients had a waddling gait. Four patients were partially wheelchair-dependent and ten patients had limitations in their maximum walking distance. In conclusion, clinically significant hip abnormalities develop in all MPS VI patients from very early in life, starting with deformities of the os ilium and acetabulum. Femoral head abnormalities occur later, most likely due to altered mechanical forces in combination with epiphyseal abnormalities due to glycosaminoglycan storage. The final shape and angle of the femoral head differs significantly between individual MPS VI patients and is difficult to predict. [ABSTRACT FROM AUTHOR]

Abstract: Maroteaux–Lamy syndrome (mucopolysaccharidosis type VI, MPS VI) is a rare progressive metabolic disorder characterized by coarse facial features, hepatosplenomegaly, restrictive pulmonary function, cardiac abnormalities and stiff joints. The disease is caused by a deficiency of the lysosomal enzyme N-acetyl galactosamine 4-sulfatase which leads to glycosaminoglycan (GAG) storage in various tissues. It presents as a clinical spectrum with varying disease progressions and severities. While the phases I/II/III studies proved the effectiveness of enzyme-replacement therapy (ERT) with recombinant human arylsulfatase B, long-term data are still scarce. Over treatment periods ranging from 1.3 to 5.4years, this prospective open-label follow-up study in 11 Dutch mucopolysaccharidosis type VI patients (age 2–18years) showed that ERT had significant positive effects on cardiac-wall diameters (IVSd and LVMI), left and right shoulder flexions (p<0.001), liver size and spleen size (p<0.001), urinary GAG excretion (p<0.001), and the scales of quality of life (motor functioning and body functioning). ERT did not affect cardiac valve regurgitation or hearing function; HRQoL decreased slightly in two domains (‘anxiety’ and ‘negative emotions’), and patients with the rapid and slow progressive forms of the disease differed with regard to baseline GAG excretion and GAG decrease during treatment. In conclusion, ERT had an effect on several clinical parameters. This effect was established in an open cohort of young mucopolysaccharidosis type VI patients. [Copyright &y& Elsevier]

Background: Pompe disease is a hereditary metabolic myopathy, for which enzyme replacement therapy (ERT) has been available since 2006. We investigated whether ERT reduces fatigue in adult patients with Pompe disease., Methods: In this prospective international observational survey, we used the Fatigue Severity Scale (FSS) to measure fatigue. Repeated measures ANOVA was used to analyze the data over time. In a subgroup of patients, we also evaluated muscle strength using the Medical Research Council Scale, measured pulmonary function as Forced Vital Capacity, and assessed depression using the Hospital Anxiety and Depression Scale., Results: We followed 163 patients for a median period of 4 years before ERT and for 3 years during ERT. Before ERT, the mean FSS score remained stable at around 5.3 score points; during ERT, scores improved significantly by 0.13 score points per year (p < 0.001). Fatigue decreased mainly in women, in older patients and in those with shorter disease duration. Patients' improvements in fatigue were moderately correlated with the effect of ERT on depression (r 0.55; CI 95% 0.07 to 0.70) but not with the effect of ERT on muscle strength or pulmonary function., Conclusions: Fatigue is a common and disabling problem in patients with early and advanced stages of Pompe disease. Our finding that ERT helps to reduce fatigue is therefore important for this patient population, irrespective of the mechanisms underlying this effect., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Introduction: Lysosomal storage disorders (LSDs) are clinically heterogeneous disorders that result primarily from lysosomal accumulation of macromolecules in various tissues. LSDs are always progressive, and often lead to severe symptoms and premature death. The identification of the underlying genetic and enzymatic defects has prompted the development of various treatment options., Areas Covered: To describe the current treatment options for LSDs, the authors provide a focused overview of their pathophysiology. They discuss the current applications and challenges of enzyme-replacement therapy, stem-cell therapy, gene therapy, chaperone therapy and substrate-reduction therapy, as well as future therapeutic prospects., Expert Opinion: Over recent decades, considerable progress has been made in the treatment of LSDs and in the outcome of patients. None of the current options are completely curative yet. They are complicated by the difficulty in efficiently targeting all affected tissues (particularly the central nervous system), in reaching sufficiently high enzyme levels in the target tissues, and by their high costs. The pathways leading from the genetic mutation to the clinical symptoms should be further elucidated, as they might prompt the development of new and ultimately curative therapies.

Background: Monitoring the time course of mortality by cause is a key public health issue. However, several mortality data production changes may affect cause-specific time trends, thus altering the interpretation. This paper proposes a statistical method that detects abrupt changes ("jumps") and estimates correction factors that may be used for further analysis., Methods: The method was applied to a subset of the AMIEHS (Avoidable Mortality in the European Union, toward better Indicators for the Effectiveness of Health Systems) project mortality database and considered for six European countries and 13 selected causes of deaths. For each country and cause of death, an automated jump detection method called Polydect was applied to the log mortality rate time series. The plausibility of a data production change associated with each detected jump was evaluated through literature search or feedback obtained from the national data producers.For each plausible jump position, the statistical significance of the between-age and between-gender jump amplitude heterogeneity was evaluated by means of a generalized additive regression model, and correction factors were deduced from the results., Results: Forty-nine jumps were detected by the Polydect method from 1970 to 2005. Most of the detected jumps were found to be plausible. The age- and gender-specific amplitudes of the jumps were estimated when they were statistically heterogeneous, and they showed greater by-age heterogeneity than by-gender heterogeneity., Conclusion: The method presented in this paper was successfully applied to a large set of causes of death and countries. The method appears to be an alternative to bridge coding methods when the latter are not systematically implemented because they are time- and resource-consuming.

A wide range of factor VIII and IX levels is observed in heterozygous carriers of hemophilia as well as in noncarriers. In female carriers, extreme lyonization may lead to low clotting factor levels. We studied the effect of heterozygous hemophilia carriership on the occurrence of bleeding symptoms. A postal survey was performed among most of the women who were tested for carriership of hemophilia in the Netherlands before 2001. The questionnaire included items on personal characteristics, characteristics of hemophilia in the affected family members, and carrier testing and history of bleeding problems such as bleeding after tooth extraction, bleeding after tonsillectomy, and other operations. Information on clotting factor levels was obtained from the hospital charts. Logistic regression was used to assess the relation of carrier status and clotting factor levels with the occurrence of hemorrhagic events. In 2004, 766 questionnaires were sent, and 546 women responded (80%). Of these, 274 were carriers of hemophilia A or B. The median clotting factor level of carriers was 0.60 IU/mL (range, 0.05-2.19 IU/mL) compared with 1.02 IU/mL (range, 0.45-3.28 IU/mL) in noncarriers. Clotting factor levels from 0.60 to 0.05 IU/mL were increasingly associated with prolonged bleeding from small wounds and prolonged bleeding after tooth extraction, tonsillectomy, and operations. Carriers of hemophilia bleed more than other women, especially after medical interventions. Our findings suggest that not only clotting factor levels at the extreme of the distribution, resembling mild hemophilia, but also mildly reduced clotting factor levels between 0.41 and 0.60 IU/mL are associated with bleeding.

Hepatitis C has a negative effect on health-related quality of life (HRQoL). It is not clear whether hepatitis C affects HRQoL of patients with hemophilia. The objective of this study was to assess the effect of hepatitis C virus (HCV) infection on HRQoL in patients with hemophilia. A cross-sectional study was performed among all registered hemophilia patients in the Netherlands. HRQoL was determined by using the self-administered SF-36 questionnaire. Patients were eligible for the study if they completed the SF-36, had been treated with clotting factor products before 1992, and had reported their hepatitis C status. Data on the severity of hemophilia were obtained from the hemophilia treatment centers. The validity of the self-reported data on hepatitis C status was verified in a random sample of 92 (15%) patients; 92% reported their hepatitis C status correctly. Fifty-five percent (333/602) of the study population had a current HCV infection. All eight domains of the SF-36 were lower in patients with a current HCV infection than they were in patients who had never been infected with HCV. After adjustment for age, severity of hemophilia, human immunodeficiency virus (HIV) status, employment status, and joint limitations, hepatitis C infection was associated with a decrease of HRQoL on the domains of general health (difference 6.9 [95% confidence interval (C.I.) 2.7 to 11.2]) and vitality (3.8 [95% C.I. 0.1 to 7.7]). Hemophilia patients infected with HCV scored lower on the HRQoL domains of general health and vitality than hemophilia patients who had never been infected with HCV.